Carbohydrate-auxiliary assisted preparation of enantiopure 1,2-oxazine derivatives and aminopolyols

Article abstract of DOI:10.3762/bjoc.8.74

An approach to enantiopure hydroxylated 2H-1,2-oxazine derivatives is presented utilizing the [3 + 3] cyclisation of lithiated alkoxyallenes and an L-erythrose-derived N-glycosyl nitrone as precursors. This key step proceeded only with moderate diastereoselectivity, but allowed entry into both enantiomeric series of the resulting 3,6-dihydro-2H-1,2-oxazines. Their enol ether double bond was then subjected to a hydroboration followed by an oxidative work-up, and finally the auxiliary was removed. The described three-step procedure enabled the synthesis of enantiopure hydroxylated 1,2-oxazines. Typical examples were treated with samarium diiodide leading to enantiopure acyclic aminopolyols. We also report on our attempts to convert these compounds into enantiopure hydroxylated pyrrolidine derivatives.

Full text of DOI:10.3762/bjoc.8.74

Carbohydrate-auxiliary assisted preparation of
enantiopure 1,2-oxazine derivatives
and aminopolyols
Marcin Jasiński1,2, Dieter Lentz1,§ and Hans-Ulrich Reissig*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 662–674.
1Institut für Chemie und Biochemie, Freie Universität Berlin,
Takustr. 3, D-14195 Berlin, Germany and 2Department of Organic
and Applied Chemistry, University of Łódź, Tamka 12, PL-91-403
Poland
doi:10.3762/bjoc.8.74
Received: 27 January 2012
Accepted: 28 March 2012
Published: 30 April 2012
Email:
Hans-Ulrich Reissig* - hreissig@chemie.fu-berlin.de
This article is part of the Thematic Series "Synthesis in the
glycosciences II".
* Corresponding author
§ Responsible for X-ray crystal-structure determination
Guest Editor: T. K. Lindhorst
Keywords:
© 2012 Jasiński et al; licensee Beilstein-Institut.
aminopolyols; carbohydrates; chiral auxiliaries; lithiated alkoxyallenes;
1,2-oxazines; pyrroles; pyrrolidines; samarium diiodide
License and terms: see end of document.
Abstract
An approach to enantiopure hydroxylated 2H-1,2-oxazine derivatives is presented utilizing the [3 + 3] cyclisation of lithiated
alkoxyallenes and an L-erythrose-derived N-glycosyl nitrone as precursors. This key step proceeded only with moderate diastereo-
selectivity, but allowed entry into both enantiomeric series of the resulting 3,6-dihydro-2H-1,2-oxazines. Their enol ether double
bond was then subjected to a hydroboration followed by an oxidative work-up, and finally the auxiliary was removed. The
described three-step procedure enabled the synthesis of enantiopure hydroxylated 1,2-oxazines. Typical examples were treated with
samarium diiodide leading to enantiopure acyclic aminopolyols. We also report on our attempts to convert these compounds into
enantiopure hydroxylated pyrrolidine derivatives.
Introduction
During the last few decades carbohydrate-derived nitrones have diastereoselectivity [9]. We previously reported on the unusu-
turned out to be particularly attractive tools for the synthesis of ally diverse synthetic potential of carbohydrate-derived 1,2-
structurally complex compounds [1-4]. Employed mainly as oxazines allowing the smooth and flexible preparation of
1,3-dipoles in cycloadditions [5,6] or as imine analogues in various highly functionalised compounds, including de novo
nucleophilic additions [7,8], these nitrones very often furnish syntheses of carbohydrates and their mimetics, as well as
the corresponding products in a highly selective manner. In this N-heterocycles [10-12]. Although the reactions of lithiated
context, reactions of lithiated alkoxyallenes with enantiopure alkoxyallenes, with nitrones bearing substituents with stereo-
nitrones are particularly of interest since they lead by a [3 + 3] genic centres at the carbon atom, were studied in our group in
cyclisation process to 1,2-oxazine derivatives with excellent great detail [13], N-glycosyl-substituted nitrones have so far not
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Beilstein J. Org. Chem. 2012, 8, 662–674.
been used as electrophiles for this purpose. This type of nitrone
has been introduced and broadly studied by Vasella and
co-workers [14-20] and has also been used by other groups [21-
25]. They observed moderate to high diastereoselectivities for
1,3-dipolar cycloadditions and for nucleophilic additions.
Successful applications of these easily removable auxiliaries in
the syntheses of biologically active agents were also reported
[26-31]. Apart from the obvious reactivity of N-glycosyl
nitrones of type 1 leading to five-membered heterocycles A or
to N,N-disubstituted hydroxylamine derivatives B, a twofold
nucleophilic addition of an excess of organometallic reagents
furnishing compounds of type C (Nu1 = Nu2) was described
and discussed by Goti et al. (Scheme 1) [32]. In selected
examples, the synthesis of differently substituted products (Nu1
≠ Nu2) was possible by consecutive additions of the appro-
priate Grignard reagents [33]. Here we report on the applica-
tion of a nitrone with an L-erythronolactone-derived auxiliary
Scheme 1: Reactivity of N-glycosyl nitrones 1 towards dipolarophiles
and nucleophiles leading to products of type A, B, C and D.
for the synthesis of 3,6-dihydro-2H-1,2-oxazine derivatives of prepared [35] and was subsequently treated with N-benzylhy-
type D. Their selected transformations, including hydrobora- droxylamine [36], and the resulting product was oxidised with
tion of the enol ether moiety, oxidative work-up, glycosyl activated MnO2 [37] to furnish the desired compound 1a in
cleavage, and samarium diiodide-induced reactions, are 51% overall yield. The initial experiment with 1a was carried
presented as well.
out under typical conditions with 2.4 equiv of lithiated
methoxyallene at −78 °C in THF. Similarly to previous results
for more rigid cyclic nitrones [38], the formation of the inter-
Results and Discussion
In continuation of our recent exploration of L-erythrose-derived mediate N-hydroxylamines 2 (Scheme 2) was clearly observed.
nitrones for the synthesis of 3,6-dihydro-2H-1,2-oxazine deriva- These primarily formed compounds were not isolated, but (in
tives [34], we turned our attention to benzaldehyde-derived the presence of a drying agent) they underwent slow cyclisation
nitrone 1a, which is readily available in a three-step procedure in Et2O solution at room temperature to furnish the desired 1,2-
starting from L-arabinose. L-Erythronolactone was first oxazine derivative as a mixture of separable diastereomers (3S)-
Scheme 2: Additions of lithiated alkoxyallenes to L-erythrose-derived nitrone 1a leading to 3,6-dihydro-2H-1,2-oxazine derivatives 3 via the respective
N-hydroxylamines 2.
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Beilstein J. Org. Chem. 2012, 8, 662–674.
Table 1: Selected reaction conditions of nitrone 1a with lithiated methoxyallene.
entry
lithiated methoxyallene (equiv)a
T (°C)
time (h)
(3S)-3a / (3R)-3a ratiob
yieldc [%]
1
2
3
4
5
6
7
10.0
3.0
2.4
2.2
1.5
2.2
2.2
−78
−78
1.0
1.0
1.0
1.0
1.0
1.0
1.5
–
3:1
3:1
3:1
2.5:1
2:1
2:1
tracesd
26
−78
33
−78
38
−78
26
−100 → −80
−130 → −80
51
75
aReactions performed in 1.1 mmol scale with respect to 1a. bCrude product. cCombined yield of isolated (3S)-3a and (3R)-3a. dOnly the major dia-
stereomer (3S)-3a was detected.
3a and (3R)-3a in 25% and 8% yield, respectively (Table 1, protons assigned to C-3 of the 1,2-oxazine ring appear as sing-
entry 3). The 1,2-oxazines were accompanied by a complex lets at 4.85 and 4.48 ppm, respectively. Due to the unhindered
mixture of by-products, from which only two compounds 4 rotation of the auxiliary moiety similar correlation peaks in
(1%) and 5 (3%) could be isolated in pure form (Figure 1). NOE experiments were observed for both isomers. Fortunately,
After tedious optimisation with respect to stoichiometry, the minor product (3R)-3a isolated as an amorphous solid could
temperature, time, concentration, etc. (selected results are be recrystallised from ethyl acetate solution to give crystals
presented in Table 1), we found that running the reaction from suitable for an X-ray crystallographic analysis (Figure 2). The
−130 to −80 °C, followed by standing overnight at room X-ray analysis of (3R)-3a shows a well-defined half-chair con-
temperature, allowed the synthesis of 3a with an overall yield of formation of the 1,2-oxazine ring, with four carbon atoms in
75% and a ratio of diastereomers of ca. 2:1 (49% and 22% after plane and with ONCC and OCCC torsion angles of −60° and
separation of the isomers, Table 1, entry 7). When the reaction 13°, respectively. The bulky N-substituent occupies a pseudo-
was scaled up to 3.50 g of 1a the expected diastereomers of 1,2- equatorial position and the phenyl group is in a pseudo-axial
oxazines 3a were obtained with no decrease in yield (78%). As position. Since characteristic shift patterns in the 1H NMR
illustrated in Scheme 2, lithiated (2-trimethylsilyl)ethoxyallene spectra for both diastereomeric series are observed, the con-
and benzyloxyallene were also examined under the optimised
reaction conditions and furnished the expected diastereomers of
1,2-oxazine derivatives 3b and 3c in 51% and 65% yield, res-
pectively.
Figure 1: By-products 4 and 5 isolated from the reaction of nitrone 1a
with lithiated methoxyallene.
The mixtures of diastereomers of crude 1,2-oxazines 3a–c were
easily separated by standard column chromatography and char-
acterised by spectroscopic methods. However, in certain cases
additional purification was necessary to obtain analytically pure
samples. The absolute configuration of the newly generated
stereogenic centre could not be determined based on NMR tech-
Figure 2: Single-crystal X-ray analysis of (3R)-3a (ellipsoids are drawn
at a 50% probability level).
niques. For instance, in the 1H NMR spectra of the diastereo-
meric products (3S)-3a and (3R)-3a, the signals of the benzylic
664

Beilstein J. Org. Chem. 2012, 8, 662–674.
figuration at C-3 of the TMSE derivatives (b) and benzyloxy HRMS and elemental analysis allowed identification of 5 as a
analogues (c) could be assigned as well with high certainty.
2,3,4,5-tetrasubstituted pyrrole derivative.
The stereochemical outcome observed for the reactions studied As shown in Table 1, entries 1–3, a higher excess of lithiated
also deserves some comment. Whereas lithiated methoxy- and methoxyallene resulted in a significant decrease in the yield of
TMS-ethoxyallene yielded the diastereomers in ca. 2:1 ratio, in 1,2-oxazine derivatives. For example, in the case of 10 equiv of
the case of lithiated benzyloxyallene a significant switch of the lithiated methoxyallene (Table 1, entry 1) only a trace amount
selectivity to an approximate 1:2 ratio was observed. According of (3S)-3a (<5%) and numerous side products were found in the
to the model proposed in the literature [7,18,20] for the add- crude product, including compound 5. On the other hand, no
ition of nucleophiles, the stereochemical course is governed by pyrrole 5 could be detected when only a slight excess of
a competition of steric and electronic effects. As presented in methoxyallene was used (Table 1, entry 5) or when the reaction
Figure 3, the bulky benzyloxy substituent favours the anti-add- was performed at lower temperatures (Table 1, entries 6 and 7).
ition and hence yields the (3R)-configured product as the major These observations prompted us to postulate that the surprising
compound. In contrast, the less hindered lithiated methoxy- formation of 5 is the result of a double addition of lithiated
allene enables a syn-attack supported by a “kinetic anomeric methoxyallene to nitrone 1a as illustrated in Scheme 3, the
effect”, stabilizing the respective transition state [20] and crucial step being the (reversible) opening of the tetrahydro-
furnishing the (3S)-configured 1,2-oxazine. In all tested furan ring of the primary addition product E. The resulting new
examples the level of diastereoselectivity was only low to nitrone F can then react with the second equiv of lithiated
moderate, and the interpretation should therefore not be exag- methoxyallene to give the double adduct G. After aqueous
gerated. Alternative conformations explaining the results are work-up, hydroxylamine derivative H underwent a ring-closure
certainly possible.
to 1,2-oxazetidine derivative I. It is known that this class of
compounds can suffer a thermally induced [2 + 2] cyclorever-
sion involving N–O bond cleavage [39,40], which, in our case,
led to the formation of methyl acrylate and imine J. This imine
underwent subsequent cyclisation to zwitterion K and two
proton shifts, probably via 3-exomethylene compound L, finally
led to pyrrole 5. This mechanism is certainly speculative but
offers a possibility to explain the formation of the tetrasubsti-
tuted pyrrole 5. The structure of the intermediate double-add-
ition product H suggests that other by-products may be formed,
e.g., two different N-allenylmethyl-substituted 3,6-dihydro-2H-
1,2-oxazines or an isomeric pyrrole derivative. The numerous
sets of signals in the 1H NMR spectrum as well as additional
spots seen on TLC of the crude reaction mixtures support this
assumption, but none of these possible by-products could be
isolated.
Figure 3: Model proposed for the addition of lithiated allenes to nitrone
1a.
The fragmentation of the primarily formed allenyl
N-hydroxylamines of type 2 leading to 1,3-dienes such as 4 With respect to the enormous importance of polyhydroxylated
(Figure 1) by retro-nitroso-ene reaction was discussed in earlier N-heterocycles as carbohydrate-mimicking glycosidase inhibi-
work [13], but the formation of pyrrole derivative 5 is unpre- tors [41-45], the introduction of an additional hydroxyl moiety
cedented for the reactions of nitrones and lithiated alkoxyal- into 1,2-oxazine derivatives was an essential goal in several
lenes. The 1H NMR spectrum of 5 shows four singlets (3H studies by our group [34,46-48]. A series of 5-hydroxy-1,2-
each) assigned to three methyl groups and one methoxy oxazine derivatives was successfully prepared by the well
substituent. Additionally, a broad singlet at δ = 8.98 ppm attrib- known hydroboration/oxidation protocol, with yields and
uted to the NH functionality, an OH group at 2.11 ppm (dd, J ≈ selectivities strongly depending on the relative configuration of
4.0, 8.1 Hz) coupling with the adjacent methylene group, and a the employed 1,2-oxazine derivative and on the presence of
characteristic set of multiplets of the [1,3]dioxolane and the additives [34,48]. In general, syn-configured 1,2-oxazines (with
phenyl moieties could be found. The signals of four quaternary respect to the relative configuration at C-3 and the neigh-
carbon atoms in the 13C NMR spectrum evidenced the pres- bouring stereogenic centre at the carbohydrate-derived C-3-
ence of the pyrrole structure. Finally, the HMBC experiment substituent) were found to be excellent substrates, leading to the
proved the proposed substitution pattern at the pyrrole ring. desired alcohols exclusively with very high degrees of stereose-
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Beilstein J. Org. Chem. 2012, 8, 662–674.
Scheme 3: Speculative mechanistic suggestion for the formation of tetrasubstituted pyrrole derivative 5.
lectivity. In an extension of these studies, selected compounds the observed low facial selectivity results predominantly from
of type 3 were hydroxylated following the general methodo- the moderate hindrance exhibited by the neighbouring phenyl
logy. As shown in Scheme 4, each of the (3S)-configured 1,2- substituent, which in the case of the (3S)-series probably occu-
oxazines 3a and 3b furnished a pair of hydroxylated products 6, pies a pseudo-equatorial position in the half-chair conformation
7 and 8, 9, respectively, in high combined yields (83% and of the 3,6-dihydro-2H-1,2-oxazine derivatives 3. The higher
93%) and almost the same ratio (approximately 3:2) of cis- stereoselectivity of the hydroboration of (3R)-3a is probably
trans/trans-trans isomers. The stereoselectivity for this series is caused by the pseudo-axial location of the phenyl group (as evi-
apparently only low. On the other hand, for (3R)-3a a ca. 3:1 denced by the X-ray analysis, Figure 2), shielding one side
ratio of hydroxylated products was observed based on the more efficiently. The carbohydrate-derived N-substituent is
1H NMR spectrum of the crude mixture; however, the minor relatively far away from the two reacting carbon atoms and very
product 10 was isolated in 13% yield only, whereas the major likely has no strong, direct influence on the observed diastereo-
product was obtained in a satisfying 66% yield. We assume that selectivities.
Scheme 4: Introduction of a 5-hydroxy group into 1,2-oxazine derivatives 3 by a hydroboration/oxidation protocol; (a) BH3·THF (4.0 equiv), THF,
−30 °C to rt, 3 h; (b) NaOH, H2O2 (30%), −10 °C to rt, overnight.
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Beilstein J. Org. Chem. 2012, 8, 662–674.
All products 6–11 obtained by the hydroboration/oxidation tetrahydro-2H-1,2-oxazine derivatives 12–15, including ent-12
protocol were easily purified and separated by column chroma- and ent-13 (Table 2). Reaction of the trans-trans-configured
tography and finally deprotected by treatment with acid. This 4-methoxy-1,2-oxazines 6 and 10 with a methanolic solution of
afforded a series of the desired, highly functionalised HCl (1 M) at elevated temperatures enabled the smooth
Table 2: Acid-induced cleavages of N- and O-protective groups of 5-hydroxy-1,2-oxazine derivatives 6–11; conditions: (a) HCl (1 M) in MeOH, 40 °C,
3.5 h; (b) DOWEX-50, EtOH, 50 °C, 4 d; (c) BBr3 (3 equiv), CH2Cl2, −78 °C (1 h) then rt, overnight.
entry
1
N-glycosyl 1,2-oxazine
conditions
(a)
product
yield
79%
mp/[α]D22
110–112 °C/
+60.1 (c 1.05,
CHCl3)
6
7
12
13
112–113 °C/
+47.9 (c 1.00,
CHCl3)
2
3
4
5
6
7
(a)
(b)a
83%
78%
75%b
84%
92%
18%
153–154 °C/
+33.8 (c 1.05,
CH3OH)
8
14
190–192 °C/
+65.6 (c 1.26,
CH3OH)
(a) then (b)
9
15
110–112 °C/
−61.5 (c 1.18,
CHCl3)
(a)
10
11
12
ent-12
ent-13
14
110–113 °C/
−48.8 (c 1.10,
CHCl3)
(a)
(c)
—c
aReaction time prolonged to 10 days; boverall yield for two steps; cmelting point and spectroscopic data correspond with the sample of compound 14
obtained from 8 (Table 2, entry 3).
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Beilstein J. Org. Chem. 2012, 8, 662–674.
cleavage of the glycosyl bond to give the N-unsubstituted options for subsequent transformations into other relevant com-
derivatives 12 and ent-12 in high yields (Table 2, entries 1 and pound classes. By reductive ring opening the corresponding
5). The cis-trans-configured compound pair 7 and 11 provided amino polyols should be accessible. Since compounds of type
similar results, yielding the expected enantiomers 13 and ent-13 12 contain a benzylamine substructure, standard methods that
(Table 2, entries 2 and 6). As expected, the enantiomers show may possibly attack this moiety, such as catalytic hydrogena-
nicely matching optical rotations with opposite sign. In the case tion, should be avoided. As an alternative, samarium diiodide is
of the TMSE-protected derivative 9, selective removal of the an attractive reagent for this purpose. Apart from its extra-
N-protective group could be achieved under the applied condi- ordinary potential for the formation of new carbon–carbon
tions. After prolonged reaction times (16 h) there was no bonds [52-54], the cleavage of N–O bonds in a chemoselective
significant change in the tested sample. A complete deprotec- fashion is also well documented [55-57]. The application of
tion of 9 leading to dihydroxylated compound 15 was possible samarium diiodide for 1,2-oxazine ring opening allowed effi-
in high overall yield (75%) by using ion-exchange resin cient syntheses of numerous polyhydroxylated heterocycles,
DOWEX-50 at 50 °C (Table 2, entry 4). As shown for com- such as pyrrolidine [46], azetidine [47], furan [58], and pyran
pound 8, simultaneous cleavage was also possible, and the derivatives [59]. Gratifyingly, the treatment of tetrahydro-2H-
analytically pure compound 14 was isolated in comparable yield 1,2-oxazine derivatives 12 and 13 with an excess of SmI2 in
(Table 2, entry 3). Alternatively, demethylation of 12 by treat- tetrahydrofuran smoothly provided the expected amino alco-
ment with boron tribromide at low temperatures [49] also hols 16 and 17 in excellent yields (Scheme 5).
provided the expected compound 14 (Table 2, entry 7); how-
ever, the analytically pure sample of this compound could only
be isolated in 18% yield. Therefore, the protocol applying a
TMS-ethyl substituent as a more easily removable O-protective
group turned out to be much more effective. All enantiopure
1,2-oxazines 12–15 were isolated as colourless crystals, which
were prone to sublimation.
The 1H NMR spectrum of trans–trans configured 14 also
deserves a short comment. Similarly to the previously described
2,4- and 2,5-dimethyltetrahydro-1,2-oxazine derivatives [50],
significant long-range couplings could be observed in the
1H NMR spectrum. The low-field shifted multiplet (4.12–4.19
ppm) assigned to the equatorial 6-H showed additional coup-
lings of <2.5 Hz. However, due to 4-H/5-H overlapping,
selective decoupling of this complex spin system was not
possible. An indirect proof for the observed phenomenon was
Scheme 5: Samarium diiodide-induced ring opening of tetrahydro-2H-
1,2-oxazine derivatives 12 and 13.
found in the 1H NMR spectrum (Supporting Information File 2)
of 14 prior to purification, i.e., still containing BBr3, which acts
here as a shift reagent. The influence of the coordinated boron
species resulted not only in a strong low-field shift but it also In order to compare the behaviour of a compound still bearing
simplified the spectrum, and thus, only geminal and vicinal the N-auxiliary, we converted tetrahydro-2H-1,2-oxazine 7 into
couplings (J = 12.2 Hz and J = 5.4 Hz) for the equatorial 6-H the O-benzylated derivative 18 under standard conditions
could be found. On the other hand, a possible nitrogen and/or (Scheme 6). Treatment of this protected compound with
ring inversion usually measurable at lower temperatures should samarium diiodide furnished a complex mixture of products
be taken into account [51]. As expected, no significant changes from which only the two amino alcohols 19 and 20 were isol-
in the shift pattern were observed in a series of 1H NMR spectra ated, in low yield. The formation of 20 could be explained by a
measured at elevated temperatures, both in methanol-d4 (up to subsequent SmI2-mediated reduction of the C=N bond formed
50 °C) and DMSO-d6 (up to 80 °C). Moreover, in the 13C NMR by ring opening of 19, which contains a hemiaminal moiety.
spectrum only one set of sharp signals was observed.
This suggestion is supported by the 1H NMR spectrum of 19 in
which a second set of signals could be easily detected. Thus, the
Due to their similarity to carbohydrate derivatives, hydroxylated direct use of 1,2-oxazine derivatives still containing the carbo-
1,2-oxazines such as 12–15 may already have interesting bio- hydrate-derived auxiliary at the nitrogen is apparently not suffi-
logical activity, but their functional groups also open several ciently selective during samarium diiodide-promoted reactions.
668

Beilstein J. Org. Chem. 2012, 8, 662–674.
Scheme 6: Reaction of tetrahydro-2H-1,2-oxazine 18 with samarium diiodide. (a) NaH (1.4 equiv), BnBr (1.2 equiv), DMF, 0 °C to rt, overnight.
The successful transformation of N-benzyl-substituted To overcome these apparent difficulties, tert-butyldimethylsilyl-
tetrahydro-2H-1,2-oxazine derivatives into polyhydroxylated protected compound 27 was prepared. Samarium diiodide-
pyrrolidine derivatives [46] prompted us to select compound 13 mediated ring opening under standard conditions furnished the
as a precursor and to examine the described methods with this expected amino alcohol 28 in excellent yield (Scheme 8). An
substrate. First, the free hydroxy group was protected as a attempted cyclisation of 28 using tosyl chloride in the presence
trimethylsilyl ether and, after SmI2-induced ring opening, the of triethylamine was not successful but led to N-tosylated com-
expected product 22 was clearly identified based on TLC moni- pound 31 in 24% yield. A partial epimerisation at the benzylic
toring. However, the attempted isolation and purification of this position and slow decomposition of precursor 28 could also be
compound by column chromatography provided amino alcohol observed under the reaction conditions applied, and none of the
17 as the only product in high yield (92%). The limited stability desired pyrrolidine derivatives could be found in the crude
of the TMS protective group is evident from the results product. Purification on a silica gel column yielded two
presented in Scheme 7. Treatment of freshly prepared unpuri- fractions containing a mixture of the C-4 epimeric N,O-di-
fied 22 with an excess of mesyl chloride and triethylamine tosylated compounds (14%, ca. 1:1 ratio) and a mixture of the
yielded a complex product mixture. The isolated compounds respective tosylamides (41%, ca. 4:1 ratio). Additional chroma-
23–26 clearly indicate that the migration of the TMS group not tography of the latter fraction enabled isolation of compound 31
only takes place in an intramolecular fashion to the terminal in the pure state (24%). Isolation of other by-products was not
hydroxy function to furnish 24, but it also occurs intermolecu- possible.
larly leading to the disilylated mesylamide 23. The desired
pyrrolidine derivative 25 was obtained only as a minor product Fortunately, the use of mesyl chloride was more efficient to
(5%). The major isolated component, N,O-dimesylated achieve cyclisation of 28. Application of this reagent afforded
pyrrolidine 26 (35%) derives from 25 by TMS-cleavage and pyrrolidine derivative 29 in acceptable overall yield. The
subsequent mesylation of the OH group.
different reaction outcome observed for the transformations of
Scheme 7: Attempted synthesis of pyrrolidine derivatives from precursor 13. (a) TMSCl (1.5 equiv), imidazole, DMAP, CH2Cl2, rt, overnight; (b) SmI2,
THF, 1.5 h, rt; (c) CHCl3, rt, overnight; (d) MsCl (4 equiv), Et3N, CH2Cl2, rt, overnight.
669

Beilstein J. Org. Chem. 2012, 8, 662–674.
Scheme 8: Synthesis of TBS-protected tetrahydro-2H-1,2-oxazine 27 and its transformation into pyrrolidine derivatives 29, 30 and 32. (a) TBSCl (2.0
equiv), imidazole, DMAP, CH2Cl2, rt, 5 d; (b) SmI2, THF, 1.5 h, rt; (c) MsCl (2.0 equiv), Et3N, CH2Cl2, rt, overnight; (d) LDA (5.4 equiv), rt, 16 h;
(e) pTsCl (2.2 equiv), Et3N, CH2Cl2, rt, overnight; (f) CBr4 (1.2 equiv), PPh3 (1.2 equiv), Et3N (1.1 equiv), CH2Cl2, rt, overnight; (g) HCl (1 M) in
MeOH, rt, 3 d.
28 with the two sulfonyl chlorides is probably a consequence of for the formation of the 1,2-oxazine ring and for the subsequent
the bulkiness of the TBS group. The small sulfene intermediate, hydroboration step. However, due to the easy separation of the
generated from mesyl chloride, smoothly reacts with the formed products by standard column chromatography, the
terminal OH group to give the respective mesylate, which presented protocol opens up access to enantiopure products with
subsequently cyclises to afford pyrrolidine 29. On the other both absolute configurations in different relative configurations,
hand, the more bulky tosyl chloride competitively attacks the in a relatively short time. The described procedure supplements
amino group. As illustrated in Scheme 8, the attempted conver- known protocols employing terpene units [62] and carbo-
sion of 29 into the free secondary amine 30 by treatment with hydrate-derived auxiliaries [63,64] for the asymmetric syn-
LDA [60] was not very efficient. The target compound was thesis of the 1,2-oxazine derivatives. More recently, the use of
accompanied by a mixture of dihydropyrrole derivatives, which (–)-menthol as a chiral auxiliary was presented for the sep-
were very likely formed by deprotonation at the benzylic pos- aration of diastereomeric 6H-1,2-oxazines [65,66]. Subsequent
ition and subsequent elimination.
transformations of the newly prepared tetrahydro-2H-1,2-
oxazines, utilizing samarium diiodide as the key reagent for the
Finally, freshly prepared unpurified 28 was subjected to the chemoselective ring opening, enable a smooth access to novel
conditions of an Appel reaction [61] providing, after 16 hours at phenyl-substituted aminopolyols. Their transformation into
room temperature, pyrrolidine derivative 30 in 33% yield. hydroxylated pyrrolidine derivatives so far proceeds only with
Again, the relatively low efficacy could be explained by the moderate efficacy, but this may certainly be optimised in the
destructive role of the base required for the subsequent cyclisa- future.
tion step. Cleavage of the TBS-moiety under acidic conditions
furnished the desired hydroxylated pyrrolidine 32 in good yield. Experimental
An attempted direct conversion of the unprotected amino diol General methods. Reactions were generally performed under
17 into 32 by treatment with tetrabromomethane in the pres- an inert atmosphere (argon) in flame-dried flasks. Solvents and
ence of triphenylphosphine gave no satisfactory results, reagents were added by syringe. Solvents were purified with a
possibly due to the formation of the corresponding oxirane and MB SPS-800-dry solvent system. Triethylamine was distilled
its diverse, subsequent reactions.
from CaH2 and stored over KOH under an atmosphere of argon.
Other reagents were purchased and used as received without
further purification unless stated otherwise. Products were puri-
Conclusion
We achieved the efficient synthesis of enantiopure hydroxylated fied by flash chromatography on silica gel (230–400 mesh,
tetrahydro-2H-1,2-oxazine derivatives using, in the key step, Merck or Fluka). Unless stated otherwise, yields refer to analyt-
lithiated alkoxyallenes and a phenyl-substituted nitrone 1a ically pure samples. NMR spectra were recorded with Bruker
bearing an L-erythronolactone-derived auxiliary as starting ma- (AC 250, AC 500, AVIII 700) and JOEL (ECX 400,
terials. Moderate levels of diastereoselectivity were observed Eclipse 500) instruments. Chemical shifts are reported relative
670

Beilstein J. Org. Chem. 2012, 8, 662–674.
to TMS or solvent residual peaks (1H: δ = 0.00 ppm [TMS], (3S,3a’S,4’S,6a’S)-2-(2’,2’-Dimethyltetrahydrofuro[3,4-
δ = 3.31 ppm [CD3OD], δ = 7.26 ppm [CDCl3]; 13C: d][1,3]dioxol-4’-yl)-4-methoxy-3-phenyl-3,6-dihydro-2H-
δ = 49.0 ppm [CD3OD], δ = 77.0 ppm [CDCl3]). Integrals [1,2]oxazine ((3S)-3a):
+133.4 (c 1.12, CHCl3); 1H NMR
are in accordance with assignments and coupling constants (CDCl3, 700 MHz) δ 1.32, 1.41 (2 s, 3H each, 2 Me), 3.47 (s,
are given in Hertz. All 13C NMR spectra are proton-decoupled. 3H, OMe), 4.03 (d, J = 9.5 Hz, 1H, 6’-H), 4.23–4.27 (ddbr, J ≈
For detailed peak assignments, 2D spectra were measured 3.5, 9.5 Hz, 1H, 6’-H), 4.30 (dd, J = 4.3, 13.7 Hz, 1H, 6-H),
(COSY, HMQC, HMBC). IR spectra were measured with a 4.40 (s, 1H, 4’-H), 4.62 (dtbr, J ≈ 2.0, 13.7 Hz, 1H, 6-H), 4.85
Nexus FT-IR spectrometer fitted with a Nicolet Smart (sbr, 1H, 3-H), 4.87 (dtbr, J ≈ 1.3, 4.3 Hz, 1H, 5-H), 4.88–4.90
DuraSample IR ATR. MS and HRMS analyses were performed (m, 2H, 3a’-H, 6a’-H), 7.26–7.33, 7.34–7.38 (2 m, 5H, Ph)
with a Varian Ionspec QFT-7 (ESI–FT ICRMS) instrument. ppm; 13C NMR (CDCl3, 126 MHz) δ 24.5, 26.3 (2 q, 2 Me),
Elemental analyses were obtained with a Vario EL or a Vario 54.8 (q, OMe), 63.5 (d, C-3), 67.3 (t, C-6), 76.6 (t, C-6’), 81.2,
EL III (Elementar Analysensysteme GmbH) instrument. 84.2 (2 d, C-3a’, C-6a’), 92.1 (d, C-5), 94.7 (d, C-4’), 111.6 (s,
Melting points were measured with a Reichert apparatus C-2’), 128.0, 128.3, 129.7, 136.2 (3 d, s, Ph), 154.9 (s, C-4)
(Thermovar) and are uncorrected. Optical rotations ([α]D) were ppm; IR (ATR) : 3085–2840 (=C-H, C-H), 1670 (C=C), 1225,
determined with a Perkin–Elmer 241 polarimeter at the 1075, 1055 (C-O) cm−1; ESI–TOF (m/z): [M + Na]+ calcd for
temperatures given. Single crystal X-ray data were collected C18H23NNaO5, 356.1474; found, 356.1479; Anal. calcd for
with a Bruker SMART CCD diffractometer (Mo Kα radiation, C18H23NO5 (333.4): C, 64.85; H, 6.95; N, 4.20; found: C,
λ = 0.71073 Å, graphite monochromator); the structure solution 64.81; H, 6.98; N, 4.15.
and refinement was performed by using SHELXS-97 [67] and
SHELXL-97 [67] in the WINGX system [68]. CCDC-864241 (3R,3a’S,4’S,6a’S)-2-(2’,2’-Dimethyltetrahydrofuro[3,4-
contains the supplementary crystallographic data for this paper. d][1,3]dioxol-4’-yl)-4-methoxy-3-phenyl-3,6-dihydro-2H-
These data can be obtained free of charge from the Cambridge [1,2]oxazine ((3R)-3a): mp 110–113 °C; crystals suitable for
Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/ X-ray analysis were obtained from AcOEt solution by cooling
data_request/cif.
(fridge); Crystal data: C18H23NO5, M = 333.37, orthorhombic,
a = 5.6042(12) Å, b = 16.756(4) Å, c = 17.839(4) Å, α =
90.00°, β = 90.00°, γ = 90.00°, V = 1675.2(6) Å3, T = 133(2) K,
space group P2(1)2(1)2(1), Z = 4, Mo Kα, 23651 reflections
measured, 4186 independent reflections (Rint = 0.0178). R1 =
0.0307 (I > 2σ(I)); wR(F2) = 0.0782 (all data); GOOF(F2) =
Typical procedure for the preparation of 1,2-
oxazine derivatives by addition of a lithiated
alkoxyallene to nitrone 1a (Procedure 1)
Lithiated methoxyallene was generated under an atmosphere of
dry argon by treating a solution of methoxyallene (357 mg,
0.42 mL, 5.06 mmol) in dry THF (20 mL) with n-BuLi (2.5 M
in hexanes; 2.0 mL, 5.0 mmol) at −40 °C. After 5 min, the
resulting mixture was cooled to −130 °C (n-pentane/liq. N2
bath), and a solution of nitrone 1a (606 mg, 2.30 mmol) in dry
THF (15 mL) was added under vigorous stirring. The partially
solidified mixture was allowed to reach −80 °C within 1.5 h and
was quenched with water. Then, warming to room temperature
was followed by extraction with Et2O (3 × 25 mL), and the
combined organic layers were stirred overnight with the drying
agent (MgSO4). When cyclisation of the primarily formed
allene adducts was complete (TLC monitoring, hexane/ethyl
acetate 4:1, p-anisaldehyde stain) the solvents were removed in
vacuo to yield a light orange oil (763 mg). The crude material
was filtered through a short silica gel pad (hexane/ethyl acetate
3:1) to yield a mixture of diastereomers (574 mg, 75%, 2:1
ratio), which were separated by column chromatography (silica
gel, hexane/ethyl acetate 7:1, gradient to 5:1) to give (3S)-3a
(380 mg, 49%, first eluted) as a pale yellow oil and (3R)-3a
(170 mg, 22%) as a colourless solid. An analytically pure
sample of (3R)-3a was obtained by recrystallisation from ethyl
acetate.
1.048.
−87.0 (c 1.36, CHCl3); 1H NMR (CDCl3, 500
MHz) δ 1.34, 1.44 (2 s, 3H each, 2 Me), 3.49 (s, 3H, OMe),
3.89 (d, J = 9.9 Hz, 1H, 6’-H), 4.03 (dd, J = 4.0, 9.9 Hz, 1H,
6’-H), 4.41 (ddd, J = 1.7, 3.2, 14.3 Hz, 1H, 6-H), 4.48 (sbr, 1H,
3-H), 4.54 (ddd, J = 1.6, 2.4, 14.3 Hz, 1H, 6-H), 4.72 (s, 1H,
4’-H), 4.80 (dd, J = 4.0, 6.1 Hz, 1H, 6a’-H), 4.90 (tbr, J ≈ 3.0
Hz, 1H, 5-H), 5.03 (d, J = 6.1 Hz, 1H, 3a’-H), 7.27–7.34,
7.36–7.40 (2 m, 5H, Ph) ppm; 13C NMR (CDCl3, 126 MHz) δ
24.7, 26.3 (2 q, 2 Me), 54.6 (q, OMe), 63.6 (d, C-3), 65.2 (t,
C-6), 74.5 (t, C-6’), 81.1 (d, C-6a’), 81.5 (d, C-3a’), 91.7 (d,
C-5), 96.4 (d, C-4’), 112.0 (s, C-2’), 127.8, 128.3, 129.0, 138.1
(3 d, s, Ph), 153.1 (s, C-4) ppm; IR (ATR) : 3060–2840 (=C-
H, C-H), 1675 (C=C), 1220, 1100, 1050 (C-O) cm−1; ESI–TOF
(m/z): [M + Na]+ calcd for C18H23NNaO5, 356.1474; found,
356.1470; Anal. calcd for C18H23NO5 (333.4): C, 64.85; H,
6.95; N, 4.20; found: C, 64.85; H, 6.83; N, 4.11.
Typical procedure for hydroborations of 1,2-
oxazines (Procedure 2)
To a solution of 1,2-oxazine (3S)-3a (268 mg, 0.80 mmol) in
dry THF (20 mL), a solution of BH3·THF (1 M in THF, 3.2 mL,
3.2 mmol) was added at −30 °C. The solution was warmed to
671

Beilstein J. Org. Chem. 2012, 8, 662–674.
Typical protocol for glycosyl bond cleavage
room temperature and stirred for 3 h, then cooled to −10 °C and
an aq NaOH solution (2 M, 4.8 mL) followed by H2O2 (30%, (Procedure 3)
1.6 mL) were added. Stirring at room temperature was 1,2-Oxazine 6 (425 mg, 1.21 mmol) was dissolved in 1 N HCl
continued overnight. After addition of a sat. aq Na2S2O3 solu- in MeOH (14 mL) and heated at 40 °C for 3.5 h (TLC moni-
tion, the layers were separated, the water layer was extracted toring, hexane/AcOEt 1:2, potassium permanganate stain). Then
with Et2O (3 × 15 mL), the combined organic layers were dried the mixture was allowed to reach room temperature, quenched
with MgSO4 and filtered, and the solvents were removed under with sat. aq NaHCO3 solution and extracted with Et2O (3 ×
reduced pressure. The crude products (321 mg, 3:2 ratio) were 30 mL). The combined organic layers were dried with MgSO4
separated by chromatography column (silica gel, hexane/ethyl and filtered, and the solvents were removed. The purification by
acetate 1:1) to give 5-hydroxy-1,2-oxazines 6 (92 mg, 33%, first column chromatography (silica gel, dichloromethane/methanol
eluted) and 7 (141 mg, 50%) as hygroscopic, colourless 40:1) yielded 12 (201 mg, 79%) as a colourless solid.
semisolids.
(3S,4S,5S)-4-Methoxy-3-phenyl-[1,2]oxazinan-5-ol (12): mp
(3S,4S,5S,3’aS,4’S,6’aS)-2-(2’,2’-Dimethyltetrahydro- 110–112 °C;
furo[3,4-d][1,3]dioxol-4’-yl)-4-methoxy-3-phenyl-[1,2]oxaz- 500 MHz) δ 3.02 (s, 3H, OMe), 3.37 (tbr, J ≈ 8.5 Hz, 1H, 4-H),
inan-5-ol (6): +131.2 (c 1.02, CHCl3); 1H NMR (CDCl3, 3.71–3.81 (m, 2H, 5-H, 6-H), 3.91 (d, J = 9.2 Hz, 1H, 3-H),
+60.1 (c 1.05, CHCl3); 1H NMR (CDCl3,
500 MHz) δ 1.28, 1.35 (2 s, 3H each, 2 Me), 2.60 (d, J = 1.9 4.14 (dd, J = 4.1, 9.7 Hz, 1H, 6-H), 2.60, 5.48 (2 sbr, 2H, NH,
Hz, 1H, OH), 2.90 (s, 3H, OMe), 3.41 (ddd, J = 1.4, 6.7, 9.4 Hz, OH), 7.31–7.38, 7.40–7.43 (2 m, 5H, Ph) ppm; 13C NMR
1H, 4-H), 3.66–3.72 (m, 2H, 5-H, 6-H), 3.93 (d, J = 9.4 Hz, 1H, (CDCl3, 126 MHz) δ 60.4 (q, OMe), 67.0 (t, C-3), 70.9 (d, C-5),
3-H), 3.93 (d, J = 9.5 Hz, 1H, 6’-H), 4.07 (dd, J ≈ 11, 16 Hz, 72.3 (t, C-6), 86.9 (d, C-4), 128.4, 128.6, 128.7, 136.3 (3 d, s,
1H, 6-H), 4.19 (dd, J = 4.4, 9.5 Hz, 1H, 6’-H), 4.41 (s, 1H, Ph) ppm; IR (ATR) : 3405–3260 (O-H, N-H), 3065–2830
4’-H), 4.81 (dd, J = 4.4, 6.1 Hz, 1H, 6a’-H), 4.86 (d, J = 6.1 Hz, (=C-H, C-H), 1105, 1055 (C-O) cm−1; ESI–TOF (m/z): [M +
1H, 3a’-H), 7.28–7.42 (m, 5H, Ph) ppm; 13C NMR (CDCl3, 126 H]+ calcd for C11H16NO3, 210.1130; found, 210.1127; Anal.
MHz) δ 24.5, 26.2 (2 q, 2 Me), 60.5 (q, OMe), 67.6 (d, C-3), calcd for C11H15NO3 (209.2): C, 63.14; H, 7.23; N, 6.69;
70.6 (d, C-5), 71.4 (t, C-6), 77.4 (t, C-6’), 81.3 (d, C-6a’), 84.4 found: C, 63.14; H, 7.23; N, 6.66.
(d, C-3a’), 87.6 (d, C-4), 94.8 (d, C-4’), 111.7 (s, C-2’), 128.3,
Typical procedure for the reactions with
128.8*, 136.8 (2 d, s, Ph) ppm; *higher intensity; IR (ATR)
:
3440 (O-H), 3090–2830 (=C-H, C-H), 1205, 1055 (C-O) cm−1; samarium diiodide (Procedure 4)
ESI–TOF (m/z): [M + Na]+ calcd for C18H25NNaO6, 374.1580; To a solution of SmI2 (ca. 0.1 M in THF, 15 mL, ~1.5 mmol) at
found, 374.1581; Anal. calcd for C18H25NO6 (351.4): C, 61.52; room temperature was added dropwise a solution of 5-hydroxy-
H, 7.17; N, 3.99; found: C, 61.43; H, 7.15; N, 3.85.
1,2-oxazine 12 (102 mg, 0.49 mmol) in degassed THF (10 mL).
After the mixture was stirred for 3 h it was quenched with sat.
(3S,4R,5R,3a’S,4’S,6a’S)-2-(2’,2’-Dimethyltetrahydro- aq sodium potassium tartrate solution and extracted with Et2O
furo[3,4-d][1,3]dioxol-4’-yl)-4-methoxy-3-phenyl-[1,2]oxaz- (20 mL), and then with CH2Cl2 (3 × 15 mL). The combined
inan-5-ol (7):
+138.2 (c 1.41, CHCl3); 1H NMR (CDCl3, organic layers were dried with MgSO4, filtered and the solvents
500 MHz) δ 1.28, 1.34 (2 s, 3H each, 2 Me), 2.44 (d, J = 7.7 were removed under reduced pressure to give the spectroscopic-
Hz, 1H, OH), 3.10 (s, 3H, OMe), 3.21 (mc, 1H, 4-H), 3.75 (sbr, ally pure product as a yellow oil in almost quantitative yield.
1H, 5-H), 3.82 (d, J = 12.2 Hz, 1H, 6-H), 3.94 (d, J = 9.4 Hz, Filtration through a short silica gel pad (dichloromethane/meth-
1H, 6’-H), 4.21 (dd, J = 4.6, 9.4 Hz, 1H, 6’-H), 4.36 (dd, J = anol 15:1) yielded 16 (97 mg, 94%) as a colourless oil.
1.4, 12.2 Hz, 1H, 6-H), 4.45 (d, J = 2.3 Hz, 1H, 3-H), 4.60 (s,
1H, 4’-H), 4.81 (tbr, J ≈ 5.2 Hz, 1H, 6a’-H), 4.94 (d, J = 6.1 Hz, (2S,3S,4S)-4-Amino-3-methoxy-4-phenylbutane-1,2-diol
1H, 3a’-H), 7.24–7.31, 7.42–7.45 (2 m, 5H, Ph) ppm; 13C NMR (16):
+12.2 (c 1.48, CHCl3); 1H NMR (CDCl3, 500 MHz)
(CDCl3, 126 MHz) δ 24.5, 26.3 (2 q, 2 Me), 59.3 (q, OMe), δ 3.31 (dd, J = 2.1, 5.3 Hz, 1H, 3-H), 3.39 (s, 3H, OMe), 3.57
62.7 (d, C-3), 65.3 (d, C-5), 71.0 (t, C-6), 77.5 (t, C-6’), 80.4 (d, (dd, J = 4.6, 11.1 Hz, 1H, 1-H), 3.72 (dd, J = 6.1, 11.1 Hz, 1H,
C-4), 81.1 (d, C-6a’), 84.5 (d, C-3a’), 95.6 (d, C-4’), 111.6 (s, 1-H), 3.77–3.80 (m, 1H, 2-H), 4.58 (d, J = 5.3 Hz, 1H, 4-H),
C-2’), 127.8, 128.3, 129.5, 136.4 (3 d, s, Ph) ppm; IR (ATR)
:
7.28–7.33, 7.36–7.43 (2 m, 5H, Ph) ppm; 13C NMR (CDCl3,
3455 (O-H), 3090–2830 (=C-H, C-H), 1215, 1085, 1050 (C-O) 126 MHz) δ 55.9 (d, C-4), 59.3 (q, OMe), 63.4 (t, C-1), 70.7 (d,
cm−1; ESI–TOF (m/z): [M + Na]+ calcd for C18H25NNaO6, C-2), 83.0 (d, C-3), 127.1, 128.1, 128.8, 138.6 (3 d, s, Ph) ppm;
374.1580; found, 374.1579; Anal. calcd for C18H25NO6 IR (ATR) : 3490–3230 (O-H, N-H), 3065–2810 (=C-H, C-H),
(351.4): C, 61.52; H, 7.17; N, 3.99; found: C, 61.43; H, 7.17; N, 1075 (C-O) cm−1; ESI–TOF (m/z): [M + H]+ calcd for
3.87.
C11H18NO3, 212.1292; found, 212.1282.
672

Beilstein J. Org. Chem. 2012, 8, 662–674.
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Supporting Information
Supporting Information File 1
Experimental procedures and characterisation data.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-74-S1.pdf]
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Supporting Information File 2
1H NMR and 13C NMR spectra of synthesised compounds.
[http://www.beilstein-journals.org/bjoc/content/
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Acknowledgements
doi:10.1002/1521-3773(20020816)41:16<3054::AID-ANIE3054>3.0.CO
;2-B
Generous support of this work by the Foundation for Polish
Science (postdoctoral fellowship to M. J.), the Deutsche For-
schungsgemeinschaft, and Bayer Healthcare is most gratefully
acknowledged. We also thank Dr. R. Zimmer for valuable
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